Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy (Brandao et al 2025)

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy
Wesley Brandao 1 , Nimansha Jain 2 3 4 , Zhuoran Yin 1 5 , Kilian L Kleemann 1 6 , Madison Carpenter 1 , Xin Bao 2 3 4 , Javier R Serrano 2 3 4 , Eric Tycksen 7 , Ana Durao 1 , Jen-Li Barry 1 , Caroline Baufeld 1 , Dilansu Guneykaya 1 , Xiaoming Zhang 1 , Alexandra Litvinchuk 2 3 4 , Hong Jiang 2 3 4 , Neta Rosenzweig 1 , Kristen M Pitts 1 5 , Michael Aronchik 1 , Taha Yahya 1 , Tian Cao 1 , Marcelo Kenzo Takahashi 1 8 , Rajesh Krishnan 1 , Hayk Davtyan 9 , Jason D Ulrich 2 3 4 , Mathew Blurton-Jones 9 , Ilya Ilin 10 , Howard L Weiner 1 11 , David M Holtzman 2 3 4 , Oleg Butovsky 1 11
Affiliations

• PMID: 39813317
• DOI: 10.1126/scitranslmed.adk3690

Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD.

Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas.

Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models.

Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

 

This is great research for Alzheimers. Finally lifting their eyes from the amyloid clumps to think about other brain processes. Could be just what they need to get this disease out of what may be the biggest dead-end in current research.

There is potentially useful spin-off for us if the research reveals more about the functions and needs of microglia. It's certainly possible microglia are involved at some point in the PEM process (whether they are working too much, too litle, are overwhelmed after the BBB breaks down ,or something else). We could benefit from a deeper understanding of microglia.